Coumarin dopamine D4 receptor antagonists

ABSTRACT

This invention relates to compounds that are antagonists of dopamine D4 receptors, to methods of treating psychosis and schizophrenia using a compound that is an antagonist of dopamine D4 receptors, and to pharmaceutically acceptable compositions that contain a dopamine D4 receptor antagonist.

FIELD OF THE INVENTION

This invention relates to compounds that are antagonists at dopamine D4receptors, to methods of treating psychosis and schizophrenia using acompound that is an antagonist at dopamine D4 receptors, and topharmaceutically acceptable compositions that contain a dopamine D4receptor antagonist.

BACKGROUND OF THE INVENTION

Dopamine is a neurotransmitter that is found in the brains of animals,including humans, and is essential for proper nerve signal transmission.It is well-known that certain compounds block or inhibit the binding ofdopamine to dopamine receptors. Such compounds are called dopaminereceptor antagonists. It is also well-known that dopamine receptorantagonists are useful in the treatment of schizophrenia and psychosis.

Recently, it has been discovered that more than one type of dopaminereceptor exists, and that dopamine receptor antagonists canpreferentially inhibit one type of dopamine receptor over another. Twomajor families of dopamine receptors have been identified and named theD1 and D2 families. In the D2 family, three distinct receptor subtypeshave been identified as D2, D3, and D4.

The distribution and concentration of the subtypes of receptors variesin different regions of the brain. D2 subtype receptors are located inboth the limbic region of the brain, which is associated with cognitionand emotional function, and in the striatum, which is associated withmotor effects. D4 receptors are found in higher concentrations in thefrontal cortex and limbic regions, which are associated with cognitiveand emotional function.

Antipsychotic drugs that are D2 subtype receptor antagonists have beenused to treat psychosis and schizophrenia, but have undesirableextrapyramidal side effects and produce tardive dyskinesia. In contrast,D4 receptor antagonists show a lack of extrapyramidal side effects andtardive dyskinesia. Moreover, it has been observed that the levels ofdopamine D4 receptors are elevated in schizophrenics.

Thus, it would be useful to have compounds that are selective D4antagonists for the treatment of psychosis and schizophrenia.

SUMMARY OF THE INVENTION

The present invention provides compounds of the Formula I ##STR1##wherein R is ##STR2## and Y is aryl, substituted aryl, heteroaryl,substituted heteroaryl, benzyl or substituted benzyl, and thepharmaceutically acceptable salts, esters, amides and prodrugs thereof.

In a preferred embodiment, R is ##STR3##

In another preferred embodiment, R is ##STR4##

In another preferred embodiment, R is ##STR5##

In another preferred embodiment, Y is phenyl.

In another preferred embodiment, Y is pyridyl.

In another preferred embodiment, Y is pyrimidinyl.

In another preferred embodiment, Y is substituted phenyl, wherein thesubstituents are selected from halogen, --CF₃, --CH₂ OH, C₁ -C₆ alkyl,--SO₂ --C₁ -C₆ alkyl, --OC₁ --C₆ alkyl, --SC₁ --C₆ alkyl, ##STR6## and--NO₂.

In still another preferred embodiment, the group R is attached to thecoumarin group at the 6 or 7 position.

Also provided by the present invention is a method of treatingpsychosis, the method comprising administering to a patient sufferingtherefrom a therapeutically effective amount of a compound of Formula I.

Also provided by the present invention is a method of treatingschizophrenia, the method comprising administering to a patientsuffering therefrom a therapeutically effective amount of a compound ofFormula I.

Also provided by the present invention is a pharmaceutically acceptablecomposition that comprises a compound of Formula I.

Also provided by the present invention are the compounds

7- 4-(3-Chloro-4-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3,4-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;

7- 4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-p-Tolyl-piperazin-1-ylmethyl!-chromen-2-one;

7-(4-Phenyl-piperidin-1-ylmethyl)-chromen-2-one;

7- 4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

2-Chloro-4-4-(2-oxo-2H-chromen-7-ylmethyl)-piperazin-1-yl!-benzaldehyde;

7-(4-p-Tolyl-piperidin-1-ylmethyl)-chromen-2-one;

7-(4-Phenyl-piperazin-1-ylmethyl)-chromen-2-one;

7- 4-(3-Nitro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-4-(4-Fluoro-3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;

7- 4-(2-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(2-Chloro-3-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3-Fluoro-phenyl)-piperazin-1-ylmethyl)-chromen-2-one;

7-(4-Naphthalen-2-yl-piperazin-1-ylmethyl)-chromen-2-one;

7- 4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

2H-1-Benzopyran-2-one, 7- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride;

7- 4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3-Propylsulfanyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(4-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-(3-Chloro-2-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7-(4-Benzyl-piperazin-1-ylmethyl)-chromen-2-one;

7- 4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

2H-1-Benzopyran-2-one, 7- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-,dihydrochloride;

7- 4-(4-tert-Butyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

7- 4-3-(Propane-1-sulfonyl)-phenyl!-piperazin-1-ylmethyl)-chromen-2-one;

6- 4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6-(4-p-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;

6-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6- 4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6-(4-(3-Chloro-phenyl)-piperazin-l-ylmethyl!-chromen-2-one;

2H-1-Benzopyran-2-one, 6- (4-phenyl-1-piperazinyl!methyl!-,monohydrochloride;

6- 4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

2H-l-Benzopyran-2-one, 6- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride;

6-14-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6- 4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6- 4-(3-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;

6-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;

6-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;

2H-1-Benzopyran-2-one, 6- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-; and

6- 4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of the Formula I ##STR7##wherein R is ##STR8## and Y is aryl, substituted aryl, heteroaryl,substituted heteroaryl, benzyl or substituted benzyl, and thepharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The term "alkyl" means a straight or branched chain hydrocarbon.Representative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term "aryl" means a cyclic aromatic hydrocarbon. Representativeexamples of aryl groups include phenyl and naphthyl.

The term "heteroaryl" means a cyclic hydrocarbon that contains one ormore heteroatom. Representative examples of heteroaryl groups arethiazole, thiophene, and pyridine and pyrimidine.

The term "heteroatom" means an atom other than carbon. Examples ofheteroatoms include nitrogen, oxygen, sulfur, and phosphorus.

The term "halogen" means chlorine, fluorine, bromine, and iodine.

The symbol "-" means a bond.

The atoms in the coumarin group can be numbered as shown below: ##STR9##

The term "patient" includes humans.

A "therapeutically effective amount" is an amount of a compound of thepresent invention that when administered to a patient ameliorates asymptom of psychosis or schizophrenia. A therapeutically effectiveamount of a compound of the present invention can be easily determinedby one skilled in the art by administering a quantity of a compound to apatient and observing the result. In addition, those skilled in the artare familiar with identifying patients having psychosis andschizophrenia and are readily able to identify patients who suffer frompsychosis and schizophrenia.

The term "pharmaceutically acceptable salts, esters, amides, andprodrugs" as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term "salts" refers to therelatively nontoxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate and laurylsulphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium and the like, aswell as nontoxic ammonium, quaternary ammonium, and amine cationsincluding, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. (See, for example, Berge S. M.,et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which isincorporated herein by reference).

Examples of pharmaceutically acceptable, nontoxic esters of thecompounds of this invention include C₁ -C₆ alkyl esters wherein thealkyl group is a straight or branched chain. Acceptable esters alsoinclude C₅ -C₇ cycloalkyl esters as well as arylalkyl esters such as,but not limited to benzyl. C₁ -C₄ alkyl esters are preferred. Esters ofthe compounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, nontoxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁ -C₆ alkyl amines and secondary C₁ -C₆ dialkyl amines wherein thealkyl groups are straight or branched chain. In the case of secondaryamines the amine may also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C₁ -C₃ alkyl primary amines and C₁ -C₂ dialkyl secondary amines arepreferred. Amides of the compounds of the invention may be preparedaccording to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

The compounds of the present invention can be administered to a patientalone or as part of a composition that contains other components such asexcipients, diluents, and carriers, all of which are well-known in theart. The compositions can be administered to humans and animals eitherorally, rectally, parenterally (intravenously, intramuscularly orsubcutaneously), intracisternally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments or drops), or as a buccal ornasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions. of a similar type may also be employed as fillers insoft- and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in-addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable nonirritating excipients or carriers such as cocoa butter,polyethyleneglycol, or a suppository wax, which are solid at ordinarytemperatures but liquid at body temperature and therefore, melt in therectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 1,000 mg per day.For a normal human adult having a body weight of about 70 kg, a dosagein the range of about 0.01 to about 100 mg/kg of body weight per day ispreferable. The specific dosage used, however, can vary. For example,the dosage can depend on a number of factors including the requirementsof the patient, the severity of the condition being treated, and thepharmacological activity of the compound being used. The determinationof optimum dosages for a particular patient is well-known to thoseskilled in the art.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The compounds of the present invention can exist in differentstereoisometric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisometric forms of thecompounds as well as mixtures thereof, including racemic mixtures, formpart of this invention.

The examples shown below illustrate particular embodiments of theinvention and are not intended to limit the specification, including theclaims, in any manner.

EXAMPLES

Synthesis

The synthesis below shows a way to make the compounds of the presentinvention.

7-(4-p-Tolyl-piperazin-1-ylmethyl)-chromen-2-one

A mixture of 6-bromomethyl coumarin (0.5 g, 2.09 mmol),4-tolylpiperazine dihydrochloride (0.51 g, 2.53 mmol) and potassiumcarbonate (2 g, 14.5 mmol) in acetonitrile (100 mL) was heated underreflux for 18 hours. The cooled mixture was filtered and concentratedunder vacuum to provide a solid. Recrystallization from ethyl acetateprovided the product as plates (0.45 g, 64% yield), mp 154-155° C.

Other derivatives were prepared similarly employing the appropriatelysubstituted piperazine, tetrahydropyridine or piperidine (startingamine) reacted with either 6- or 7-bromomethyl coumarin.

Below are tables that show the starting materials.7-Bromomethyl-coumarin can be prepared by well-known procedures (see,for example, D. O. Shah, et al., Indian J. Chem., 1974;12(9):1014)employing radical bromination of 7-methylcoumarin by N-bromosuccinimide.6-Bromomethyl-coumarin can be prepared in a similar fashion from6-methylcoumarin and N-bromosuccinimide.

The following examples were prepared by the above procedure employing7-bromomethyl coumarin except that the 4-tolylpiperazine was replacedwith the following amines:

    ______________________________________    Starting Amine    Product 7-Coumarins    ______________________________________    (3-Chloro-methyl- 7- 4-(3-Chloro-4-methyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(3-Chloro-4-    7- 4-(3-Chloro-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(3,4-Dimethyl-  7- 4-(3,4-Dimethyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(o-Tolyl)-piperazine                      7-(4-o-Tolyl-piperazin-1-                      ylmethyl)-chromen-2-one    1-(2-chloro-phenyl)-                      7- 4-(2-Chloro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(p-Tolyl)-piperazine                      7-(4-p-Tolyl-piperazin-1-                      ylmethyl)-chromen-2-one    1-Phenyl-piperidine                      7-(4-Phenyl-piperidin-1-                      ylmethyl)-chromen-2-one    1-(2,3-Dimethyl-  7- 4-(2,3-Dimethyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(3-Chloro-phenyl)-                      7- 4-(3-Chloro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(3-Trifluoromethyl-                      7- 4-(3-Trifluoromethyl-    phenyl)-piperazin phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    2-Chloro-4-(1-    2-Chloro-4- 4-(2-oxo-2H-    piperazinyl)-     chromen-7-ylmethyl)-    benzaldehyde      piperazin-1-yl!-                      benzaldehyde    1-(p-Tolyl)-piperidine                      7-(4-p-Tolyl-piperidin-1-                      ylmethyl)-chromen-2-one    1-Phenyl-piperazine                      7-(4-Phenyl-piperazin-1-                      ylmethyl)-chromen-2-one    1-(3-Nitro-phenyl)-                      7- 4-(3-Nitro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(4-Fluoro-3-    7- 4-(4-Fluoro-3-    trifluoromethyl)- trifluoromethyl-phenyl)-    phenyl)-piperazine                      piperazin-1-ylmethyl!-                      chromen-2-one    1-(3-Fluoro-4-    7- 4-(3-Fluoro-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-phenyl)    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(m-Tolyl)-piperazine                      7-(4-m-Tolyl-piperazin-1-                      ylmethyl)-chromen-2-one    1-(2-Fluoro-phenyl)-                      7- 4-(2-Fluoro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(3-Bromo-4-     7- 4-(3-Bromo-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(2-Chloro-3-    7- 4-(2-Chloro-3-methyl-    methylphenyl) -   phenyl)-piperazin-1-    piperazine        ylmethyl!-chromen-2-one    1-(2,3-Dichloro-  7- 4-(2,3-Dichloro-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(3-Fluoro-phenyl)-                      7- 4-(3-Fluoro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(2-Naphthyl)-   7-(4-Naphthalen-2-yl-    piperazine        piperazin-1-ylmethyl)-                      chromen-2-one    1-(4-Fluoro-phenyl)-                      7- 4-(4-Fluoro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(2-pyridinyl)-  2H-1-Benzopyran-2-one,    piperazine        7-  4-(2-pyridinyl)-1-                      piperazinyl!methyl!-,                      dihydrochloride    1-(4-Methoxy-phenyl)-                      7- 4-(4-Methoxy-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(3-Propylsulfanyl-                      7- 4-(3-Propylsulfanyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(4-Chloro-phenyl)-                      7- 4-(4-Chloro-phenyl)-    piperazine        piperazin-1-ylmethyl!-                      chromen-2-one    1-(3-Chloro-2-methyl-                      7- 4-(3-Chloro-2-methyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-Benzyl-piperazine                      7-(4-Benzyl-piperazin-1-                      ylmethyl)-chromen-2-one    1-(3,4,5-Trimethoxy-                      7- 4-(3,4,5-Trimethoxy-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1-(2-pyrimidinyl)-                      2H-1-Benzopyran-2-one,    piperazine        7-  4-(2-pyrimidinyl)-1-                      piperazmyl!methyl!-,                      dihydrochloride    1-(4-tert-Butyl-  7- 4-(4-tert-Butyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-one    1- 3-(Propane-1-  7-{4- 3-(Propane-1-    sulfonyl)-phenyl!-                      sulfonyl)-phenyl!-    piperazine        piperazin-1-ylmethyl}-                      chromen-2-one    ______________________________________

The following compounds were prepared using the above procedure exceptsubstituting 6-bromomethyl coumarin for 7-bromomethyl coumarin and thespecified amine for 4-tolylpiperazine.

    ______________________________________    Starting Amine    Product 6-Coumarins    ______________________________________    1-(2,3-Dimethyl-  6- 4-(2,3-Dimethyl-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(p-Tolyl)-piperazine                      6-(4-p-Tolyl-                      piperazin-1-                      ylmethyl)-chromen-2-                      one    1-(3-Bromo-4-     6- 4-(3-Bromo-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-    piperazine        phenyl)-piperazin-1-                      ylmethyl!chromen-2-                      one    1-(3-Chloro-4-    6- 4-(3-Chloro-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(2,3-Dichloro-  6- 4-(2,3-Dichloro-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(3-Fluoro-4-    6- 4-(3-Fluoro-4-    hydroxymethyl-phenyl)-                      hydroxymethyl-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(3-Chloro-phenyl)-                      6- 4-(3-Chloro-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-Phenylpiperazine                      2H-1-Benzopyran-2-                      one, 6- (4-phenyl-1-                      piperazinyl)methyl!-,                      monohydrochloride    1-(2-Chloro-phenyl)-                      6- 4-(2-Chloro-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(2-pyridinyl)-1-                      2H-1-Benzopyran-2-    piperazine        one, 6-  4-(2-                      pyridinyl)-1-                      piperazinyl!methyl!-,                      dihydrochloride    1-(2,3-Dichloro-  6- 4-(2,3-Dichloro-    phenyl)-piperazine                      phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(4-Fluoro-phenyl)-                      6- 4-(4-Fluoro-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(3-Methoxy-phenyl)-                      6- 4-(3-Methoxy-    piperazine        phenyl)-piperazin-1-                      ylmethyl!-chromen-2-                      one    1-(o-Tolyl)-piperazine                      6-(4-o-Tolyl-                      piperazin-1-                      ylmethyl)-chromen-2-                      one    1-(m-Tolyl)-piperazine                      6-(4-in-Tolyl-                      piperazin-1-                      ylmethyl)-chromen-2-                      one    1-(2-pyrimidinyl)-                      2H-1-Benzopyran-2-    piperazine        one, 6-  4-(2-                      pyrimidinyl)-1-                      piperazinyl!methyl!-    1-(3,4,5-Trimethoxy-                      6- 4-(3,4,5-    phenyl)-piperazine                      Trimethoxy-phenyl)-                      piperazin-1-                      ylmethyl!-chromen-2-                      one    ______________________________________

BIOLOGICAL METHODS

Cell Lines Expressing Dopamine Receptor Isoforms

A cell line expressing human dopamine D2 (Long form) receptors waspurchased from Oregon Health Sciences University, Portland, Ore. The D2receptor cDNA was subcloned into an expression vector, pRc/CMV. Theplasmids were transfected by electroporation into CHO K1 cells. A singlestable transfectant, resistant to the antibiotic G418, was isolated andselected for use in the binding studies. For D4 binding, CHO K1 cellsstably transfected to express the human recombinant dopamine D4.2receptor subtype, as described by Shih, et al., "The expression andfunctional characterization of human dopamine D4.2 receptor in CHO K1cells," Soc. Neurosci., 1995;21(Part 1):621.

Cell Culture and Preparation of Cell Membranes

CHO K1 cells expressing either human D2 and D4.2 receptors were grown in162 cm² culture flasks in F12 medium (Gibco Laboratories, Grand Island,N.Y.) supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT)in an atmosphere of 5% Co₂ /95% air at 37° C. Cells were grown untilconfluent, after which growth medium was removed and replaced with 0.02%ethylene diamine tetracetate (EDTA) in a phosphate-buffered salinesolution (Sigma Chemical Co; St. Louis, Mo.) and scraped from theflasks. The cells were centrifuged at about 1000×g for 10 minutes at 40°C. and then resuspended in TEM buffer (25 mM Tris-HCL, pH 7.4, 5 mMEDTA, and 6 mM MgCl₂) for D2 or the D4.2 buffer (50 mM Tris-HCl, pH 7.4,5 mM EDTA, 1.5 mM CaCl₂, 5 mM KCl, and 120 mM NaCl) and homogenized. Themembranes were pelleted by centrifugation at 20,000×g at 40° C. for 20minutes. Then the pellets were resuspended in an appropriate buffer at 1mL/flask and stored at -70° C. until used in the receptor binding assay.

Receptor Binding Assays: D2, D4.2 Dopamine Receptors

A cell membrane preparation (400 μL) was incubated in triplicate with 50μL ³ H!spiperone (0.2 nM for D2, 0.2 nM for D4.2), 50 μL buffer, orcompeting drugs where appropriate to give a final volume of 0.5 mL.After 60 minutes incubation at 25° C., the incubations were terminatedby rapid filtration through Whatmann GF/B glass fibre filters (soakedfor 1 hour in 0.5% polyethylenimine) on a -cell harvester, with threewashes of 1 mL ice-cold buffer. Individual filter disks containing thebound ligand were placed in counting vials with 4 mL of scintillationfluid (Ready Gel, Beckman Instrument Inc, Fullerton, Calif.) and thencounted in a Beckman LS-6800 liquid scintillation counter at anefficiency of 45%. Nonspecific binding was defined in presence of 1 mMof haloperidol.

Data Calculation

Saturation and competition binding data were analyzed using an iterativenonlinear least-square curve-fitting Ligand program. In competitionexperiments, apparent K_(I) values were calculated from IC₅₀ values bymethod of Cheng and Prusoff, "Relationship between the inhibitionconstant (K_(i)) and the concentration of inhibitor which causes 50%inhibition (IC₅₀) of an enzymatic reaction," Biochem. Pharmacol.,1973;22:3099-3108. Experimental compounds were made up as stocksolutions in dimethyl sulfoxide (DMSO). The final concentration of 0.1%DMSO used in the incubation mixture had no effect on the specificbinding. Each observation was carried out in triplicate. To allow thesecalculations, K_(d) values were measured for the interaction of variousligands with the receptor. These were: ³ H!spiperone binding, human D2,0.116+0.01 and human D4.2, 0.093+0.005 nM (n=3). The test results arepresented below.

    ______________________________________                          melting    Example               point (mp)                                    D4 Ki,                                          D2 Ki,    Number Name           (° C.)                                    nM    nM    ______________________________________    7-Coumarins     1     7- 4-(3-Chloro-4-methyl-                          128-9     6.9   >5882           phenyl)-piperazin-1-yl-  2           methyl!-chromen-2-one     2     7- 4-(3-Chloro-4-                           169-170  11    10565           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one     3     7- 4-(3,4-Dimethyl-                          175-6     13.9   433           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one     4     7-(4-o-Tolyl-piperazin-                          143-4     16.3  1942           1-ylmethyl)-chromen-2-           one     5     7- 4-(2-Chloro-phenyl)-                          133-5     16.8   635           piperazin-1-ylmethyl!-           chromen-2-one     6     7-(4-p-Tolyl-piperazin-                          151-2     16.9  5826           1-ylmethyl!-chromen-2-           one     7     7-(4-Phenyl-piperidin-1-                          121-3     18     91           ylmethyl)-chromen-2-one     8     7- 4-(2,3-Dimethyl-                          140-1     19     688           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one     9     7- 4-(3-Chloro-phenyl)-                          124-5     23    >10000           piperazin-1-ylmethyl!-           chromen-2-one    10     7- 4-(3-Trifluoromethyl-                           97-8     24    5882           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    11     2-Chloro-4- 4-(2-oxo-                          145-6     24.6  >5882           2H-chromen-7-yl-           methyl)-piperazin-1-yl!-           benzaldehyde    12     7-(4-p-Tolyl-piperidin-1-                          168-9     25.7           ylmethyl)-chromen-2-one    13     7-(4-Phenyl-piperazin-1-                          156-8     26    5342           ylmethyl)-chromen-2-one    14     7- 4-(3-Nitro-phenyl)-                          134-5     26    5882           piperazin-1-ylmethyl!-           chromen-2-one    15     7- 4-(4-Fluoro-3-tri-                          108-9     27.3  7118           fluoromethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    16     7- 4-(3-Fluoro-4-                          110-1     29.9           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    17     7-(4-m-Tolyl-piperazin-                          105-6     32    4401           1-ylmethyl)-chromen-2-           one    18     7- 4-(2-Fluoro-phenyl)-                          162-3     33    1002           piperazin-1-ylmethyl!-           chromen-2-one    19     7- 4-(3-Bromo-4-                          171-2     39.5           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    20     7- 4-(2-Chloro-3-methyl-                          153-4     40    5882           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    21     7- 4-(2,3-Dichloro-                          165-7     41.1  1840           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    22     7- 4-(3-Fluoro-phenyl)-                          122-3     44    4023           piperazin-1-ylmethyl!-           chromen-2-one    23     7-(4-Naphthalen-2-yl-                          186-7     49.7           piperazin-1-ylmethyl)-           chromen-2-one    24     7- 4-(4-Fluoro-phenyl)-                          137-8     59           piperazin-1-ylmethyl!-           chromen-2-one    25     2H-1-Benzopyran-2-one,   68.2  >5882           7-  4-(2-pyridinyl)-1-   4           piperazinyl!methyl!-,           dihydrochloride    26     7- 4-(4-Methoxy-                          162-3     75           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    27     7- 4-(3-Propyl-                           118-120  91           sulfanyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    28     7- 4-(4-Chloro-phenyl)-                          143-4     93           piperazin-1-ylmethyl!-           chromen-2-one    29     7- 4-(3-Chloro-2-methyl-                          140-1     128           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    30     7-(4-Benzyl-piperazin-1-                           138-40   2664           ylmethyl)-chromen-2-one    31     7- 4-(3,4,5-Trimethoxy-                          143-5     >2000           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    32     2H-1-Benzopyran-2-one,   5000           7-  4-(2-pyrimidinyl)-           1-piperazinyl!methyl!-,           dihydrochloride    33     7- 4-(4-tert-Butyl-                          174-5           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    34     7- 4- 3-(Propane-1-                          143-5           sulfonyl)-phenyl!-           piperazin-1-ylmethyl!-           chromen-2-one    6-Coumarins    35     6- 4-(2,3-Dimethyl-                          165-6     8.8   3248           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    36     6-(4-p-Tolyl-piperazin-1-                          154-5     10.9  5826           ylmethyl)-chromen-2-one    37     6- 4-(3-Bromo-4-                          125-6     12.6  2975           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    38     6- 4-(3-Chloro-4-                          177-9     13    7294           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    39     6- 4-(2,3-Dichloro-                           149-50   15    1196           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    40     6- 4-(3-Fluoro-4-                          171-2     18    >5882           hydroxymethyl-phenyl)-           piperazin-1-ylmethyl!-           chromen-2-one    41     6- 4-(3-Chloro-phenyl)-                          145-6     19.4  3323           piperazin-1-ylmethyl!-           chromen-2-one    42     2H-1-Benzopyran-2-one,                          251       21.6  >10000           6- (4-phenyl-1-           piperazinyl)methyl!-,           monohydrochloride    43     6- 4-(2-Chloro-phenyl)-                          125-6     28     218           piperazin-1-ylmethyl!-           chromen-2-one    44     2H-1-Benzopyran-2-one,                           195-201  29.7  2166           6-  4-(2-pyridinyl)-1-           piperazinyl!methyl!-,           dihydrochloride    45     6-14-(2,3-Dichloro-                           97-8     41           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    46     6- 4-(4-Fluoro-phenyl)-                          173-4     41           piperazin-1-ylmethyl!-           chromen-2-one    47     6- 4-(3-Methoxy-                          163-5     57    7118           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    48     6-(4-o-Tolyl-piperazin-1-                          131-2     63    1212           ylmethyl)-chromen-2-one    49     6-(4-m-Tolyl-piperazin-                           149-50   74           1-ylmethyl)-chromen-2-           one    50     2H-1-Benzopyran-2-one,                          192-4     163.4 23%           6-  4-(2-pyrimidinyl)-           1-piperazinyl!methyl!-    51     6- 4-(3,4,5-Trimethoxy-                          184-5     316           phenyl)-piperazin-1-yl-           methyl!-chromen-2-one    ______________________________________

We claim:
 1. The compound ##STR10##
 2. A method of treating psychosis,the method comprising administering to a patient suffering therefrom atherapeutically effective amount of a compound of Formula I wherein R is##STR11## and Y is substituted phenyl, phenyl, naphthyl, pyridyl,pyrimidinyl, or benzyl, wherein the substituents are selected fromhalogen, --CF₃, --CH₂ OH, --C₁ -C₆ alkyl, --SO₂ --C₁ -C₆ alkyl, --OC₁--C₆ alkyl, --SC₁ --C₆ alkyl, ##STR12## and NO₂, or the pharmaceuticallyacceptable salts thereof.
 3. A method of treating schizophrenia, themethod comprising administering to a patient suffering therefrom atherapeutically effective amount of a compound of formula I ##STR13##wherein R is ##STR14## and Y is substituted phenyl, phenyl, naphthyl,pyridyl, pyrimidinyl, or benzyl, wherein the substituents are selectedfrom halogen, --CF₃, --CH₂ OH, --C₁ -C₆ alkyl, --SO₂ --C₁ -C₆ alkyl,--OC₁ --C₆ alkyl, --SC₁ --C₆ alkyl, ##STR15## and N0₂, or thepharmaceutically acceptable salts thereof.
 4. The method of claim 2,wherein the compound of Formula I is7-4-(3-Chloro-4-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7- 4-(3,4-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-p-Tolyl-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2-Chloro-4-4-(2-oxo-2H-chromen-7-ylmethyl)-piperazin-1-yl!-benzaldehyde;7-(4-Phenyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(3-Nitro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(4-Fluoro-3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(2-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7- 4-(2-Chloro-3-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-Naphthalen-2-yl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 7- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride; 7-4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Propylsulfanyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(4-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-2-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-Benzyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 7- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-,dihydrochloride; 7-4-(4-tert-Butyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-{4-3-(Propane-1-sulfonyl)-phenyl!-piperazin-1-ylmethyl}-chromen-2-one; 6-4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-(4-p-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 6-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6- 4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6- 4-(3-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 6- (4-phenyl-1-piperazinyl)methyl!-,monohydrochloride; 6-4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 6- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride; 6-4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(3-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;6-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 2H-1-Benzopyran-2-one,6- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-; or 6-4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one.
 5. Themethod of claim 3, wherein the compound of Formula I is7-4-(3-Chloro-4-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7- 4-(3,4-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-p-Tolyl-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2-Chloro-4-4-(2-oxo-2H-chromen-7-ylmethyl)-piperazin-1-yl!-benzaldehyde;7-(4-Phenyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(3-Nitro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(4-Fluoro-3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(2-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7- 4-(2-Chloro-3-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-Naphthalen-2-yl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 7- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride; 7-4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Propylsulfanyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(4-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-4-(3-Chloro-2-methyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;7-(4-Benzyl-piperazin-1-ylmethyl)-chromen-2-one; 7-4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 7- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-,dihydrochloride; 7-4-(4-tert-Butyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 7-{4-3-(Propane-1-sulfonyl)-phenyl!-piperazin-1-ylmethyl}-chromen-2-one; 6-4-(2,3-Dimethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-(4-p-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 6-4-(3-Bromo-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-4-(3-Chloro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6- 4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(3-Fluoro-4-hydroxymethyl-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6- 4-(3-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 6- (4-phenyl-1-piperazinyl)methyl!-,monohydrochloride; 6-4-(2-Chloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;2H-1-Benzopyran-2-one, 6- 4-(2-pyridinyl)-1-piperazinyl!methyl!-,dihydrochloride; 6-4-(2,3-Dichloro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl!-chromen-2-one; 6-4-(3-Methoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one;6-(4-o-Tolyl-piperazin-1-ylmethyl)-chromen-2-one;6-(4-m-Tolyl-piperazin-1-ylmethyl)-chromen-2-one; 2H-1-Benzopyran-2-one,6- 4-(2-pyrimidinyl)-1-piperazinyl!methyl!-; or 6-4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-ylmethyl!-chromen-2-one.
 6. Themethod of claim 2 wherein, in the compounds of Formula I, R is attachedto the coumarin group at the 6 or 7 position.
 7. The method of claim 3wherein, in the compounds of Formula I, R is attached to the coumaringroup at the 6 or 7 position.
 8. The method of claim 2 wherein, in thecompounds of Formula I, Y is phenyl.
 9. The method of claim 3 wherein,in the compounds of formula I, Y is phenyl.
 10. The method of claim 2wherein, in the compounds of Formula I, Y is pyridyl.
 11. The method ofclaim 3 wherein, in the compounds of Formula I, Y is pyridyl.
 12. Themethod of claim 2 wherein, in the compounds of Formula I, Y ispyrimidinyl.
 13. The method of claim 3 wherein, in the compounds ofFormula I, Y is pyrimidinyl.
 14. The method of claim 2 wherein, in thecompounds of Formula I, Y is substituted phenyl and the substituents areselected from halogen, --CF₃, --CH₂ H, --C₁ -C₆ alkyl, --SO₂ --C₁ -C₆alkyl, --OC₁ --C₆ alkyl, --SC₁ --C₆ alkyl, ##STR16## and NO₂, or thepharmaceutically acceptable salts thereof.
 15. The method of claim 3wherein, in the compounds of Formula I, Y is substituted phenyl and thesubstituents are selected from halogen, --CF₃, --CH₂ OH, --C₁ -C₆ alkyl,--SO₂ --C₁ -C₆ alkyl, --OC₁ --C₆ alkyl, --SC₁ --C₆ alkyl, ##STR17## andNO₂, or the pharmaceutically acceptable salts thereof.